CNS Neuroscience & Therapeutics
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2023
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IF 5.5
Xin Li,Huimei Shi,Di Zhang,Bei Jing,Zhenni Chen,Yachun Zheng,Shiquan Chang,Li Gao,Guoping Zhao
Background This study aimed to investigate the potential mechanism of paeonol in the treatment of neuropathic pain. Methods Relevant mechanisms were explored through microglial pseudotime analysis and the use of specific inhibitors in cell experiments. In animal experiments, 32 SD rats were randomly divided into the sham operation group, the chronic constrictive injury (CCI) group, the ibuprofen group, and the paeonol group. We performed behavioral testing, ELISA, PCR, Western blotting, immunohistochemistry, and immunofluorescence analysis. Results The pseudotime analysis of microglia found that RhoA, Rock1, and p38MAPK were highly expressed in activated microglia, and the expression patterns of these genes were consistent with the expression trends of the M1 markers CD32 and CD86. Paeonol decreased the levels of M1 markers (IL1β, iNOS, CD32, IL6) and increased the levels of M2 markers (IL10, CD206, ARG-1) in LPS-induced microglia. The expression of iNOS, IL1β, RhoA, and Rock1 was significantly increased in LPS-treated microglia, while paeonol decreased the expression of these proteins. Thermal hyperalgesia occurred after CCI surgery, and paeonol provided relief. In addition, paeonol decreased the levels of IL1β and IL8 and increased the levels of IL4 and TGF-β in the serum of CCI rats. Paeonol decreased expression levels of M1 markers and increased expression levels of M2 markers in the spinal cord. Paeonol decreased IBA-1, IL1β, RhoA, RhoA-GTP, COX2, Rock1, and p-p38MAPK levels in the spinal dorsal horn. Conclusion Paeonol relieves neuropathic pain by modulating microglial M1 and M2 phenotypes through the RhoA/p38 MAPK pathway.
研究领域:
药理学
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神经科学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Di Wu,Tiancheng Gong,Zhongxiang Sun,Xihao Yao,Dongzhi Wang,Qiyang Chen,Qingsong Guo,Xiaohong Li,Yibing Guo,Yuhua Lu
The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by deposition of desmoplastic matrix (including collagen and hyaluronic acid). And the interactions between tumor-associated macrophages (TAMs) and tumor cells play a crucial role in progression of PDAC. Hence, the appropriate model of tumor cell-macrophage interaction within the unique PDAC TME is of significantly important. To this end, a 3D tumor niche based on dual-crosslinking gelatin methacrylate and hyaluronic acid methacrylate hydrogels was constructed to simulate the desmoplastic tumor matrix with matching compressive modulus and composition. The bionic 3D tumor niche creates an immunosuppressive microenvironment characterized by the downregulation of M1 markers and upregulation of M2 markers in TAMs. Mechanistically, RNA-seq analysis revealed that the PI3K-AKT signaling pathway might modulate the phenotypic balance and recruitment of macrophages through regulating SELE and VCAM-1. Furthermore, GO and GSEA revealed the biological process of leukocyte migration and the activation of cytokine-associated signaling were involved. Finally, the 3D tumor-macrophage niches with three different ratios were fabricated which displayed increased M2-like polarization and stemness. The utilization of the 3D tumor niche has the potential to provide a more accurate investigation of the interplay between PDAC tumor cells and macrophages within an in vivo setting.
研究领域:
癌症生物学
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组织工程
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生物材料
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免疫学
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细胞信号传导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY
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2018
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IF 4.185
Qiuping Zhong,Hui Yu,Chang Huang,Jiahong Zhong,Haitao Wang,Jiangping Xu,Yufang Cheng
The canonical phosphodiesterase 4 (PDE4) inhibitors produce antidepressant-like effects in a variety of animal models. However, severe side effects, particularly vomiting and nausea, limit their clinical application. FCPR16 is a novel PDE4 inhibitor with less vomiting potential. However, whether it will exert an antidepressant-like effect remains unclear. Here, we aimed to evaluate the effect of FCPR16 in mice subjected to chronic unpredictable mild stress (CUMS). Our results showed that FCPR16 produced antidepressant-like effects in multiple behavioral tests, including a forced swimming test, tail suspension test , sucrose preference test and novelty suppression feeding test. Simultaneously, data indicated that FCPR16 enhanced the levels of several proteins, including cAMP, brain derived neurotrophic factor , exchange protein directly activated by cAMP 2 (EPAC-2), synapsin1, postsynaptic density protein 95 , phosphorylated cAMP response element binding protein and extracellular regulated protein kinases 1/2, which were downregulated by CUMS in both the cerebral cortex and hippocampus . The number of DCX + cells in the hippocampus of CUMS mice was increased after FCPR16 treatment. Moreover, treatment with FCPR16 resulted in decreased expression of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and increased expression of anti-inflammatory cytokines (IL-10) in mice challenged with CUMS. Consistently, the mRNA levels of microglial M1 markers (iNOS and TNF-α) were downregulated, while M2 markers (Arginase 1 and CD206) were upregulated in CUMS-exposed mice after FCPR16 treatment. Immunofluorescence analysis showed that FCPR16 inhibited the activation of microglial cells and increased the number of CD206 + in CUMS-exposed mice. Collectively, these results suggested that FCPR16 is a potential compound with effects against depressive-like behaviors , and the antidepressant-like effect of FCPR16 is possibly mediated through activation of the cAMP-mediated signaling pathways and inhibition of neuroinflammation in both the cerebral cortex and hippocampus.
研究领域:
药理学
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神经科学
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行为科学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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